Dataset Information

Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium.

ABSTRACT: Chronic inflammatory process in the nasal mucosa is correlated with poor smell perception. Over-activation of immune cells in the olfactory epithelium (OE) is generally associated with loss of olfactory function, and topical steroidal anti-inflammatory drugs have been largely used for treating such condition. Whether this therapeutic strategy could directly affect the regenerative process in the OE remains unclear. In this study, we show that nasal topical application of dexamethasone (DEX; 200 or 800 ng/nostril), a potent synthetic anti-inflammatory steroid, attenuates OE lesion caused by Gram-negative bacteria lipopolysaccharide (LPS) intranasal infusion. In contrast, repeated DEX (400 ng/nostril) local application after lesion establishment limited the regeneration of olfactory sensory neurons after injury promoted by LPS or methimazole. Remarkably, DEX effects were observed when the drug was infused as 3 consecutive days regimen. The anti-inflammatory drug does not induce OE progenitor cell death, however, disturbance in mammalian target of rapamycin downstream signaling pathway and impairment of protein synthesis were observed during the course of DEX treatment. In addition, in vitro studies conducted with OE neurospheres in the absence of an inflammatory environment showed that glucocorticoid receptor engagement directly reduces OE progenitor cells proliferation. Our results suggest that DEX can interfere with the intrinsic regenerative cellular mechanisms of the OE, raising concerns on the use of topical anti-inflammatory steroids as a risk factor for progressive olfactory function impairment.

SUBMITTER: Crisafulli U

PROVIDER: S-EPMC5845685 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium.

Crisafulli Umberto U Xavier André M AM Dos Santos Fabiana B FB Cambiaghi Tavane D TD Chang Seo Y SY Porcionatto Marimélia M Castilho Beatriz A BA Malnic Bettina B Glezer Isaias I

Frontiers in molecular neuroscience 20180306

Chronic inflammatory process in the nasal mucosa is correlated with poor smell perception. Over-activation of immune cells in the olfactory epithelium (OE) is generally associated with loss of olfactory function, and topical steroidal anti-inflammatory drugs have been largely used for treating such condition. Whether this therapeutic strategy could directly affect the regenerative process in the OE remains unclear. In this study, we show that nasal topical application of dexamethasone (DEX; 200 ...[more]

PMID: 29559887

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Project description:BackgroundAutism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice.MethodsWe used Tbr1 +/- mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1 +/- mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation.ResultsTbr1 +/- mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1 +/- olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1 +/- mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1 +/- mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency.ConclusionsTbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1 +/- mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.

Dataset Information

Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium.

Publications

Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium.

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